RU2640023C2 - Liquid composition - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention is an oral bio-available non-aqueous liquid composition containing at least 7 wt % of propylene glycol in the total composition weight, a cardiotonic means, or angiotensin-converting enzyme inhibitor, or combination of cardiotonic means and angiotensin-converting enzyme inhibitor. Invention discloses a method for obtaining the composition described above, by mixing at least 7 wt % of propylene glycol by the total composition weight with a cardiotonic means, or angiotensin-converting enzyme inhibitor, or a combination of cardiotonic means with angiotensin-converting enzyme inhibitor.

EFFECT: treatment of heart disease and hypertension.

34 cl, 11 dwg, 17 tbl, 2 ex

Description

Technical field

The present invention relates to a liquid composition, in particular a liquid composition containing a cardiotonic agent, preferably pimobendan, and / or an angiotensin converting enzyme inhibitor, preferably enalapril or benazepril, for use in treating heart disease and / or hypertension in mammals, in particular dogs or cats.

State of the art

Heart disease and / or hypertension are becoming more common problems in animals, especially companion animals and animals in a zoo. For example, it is estimated that approximately 10% of domestic dogs suffer from heart disease. Common heart diseases in dogs include primary or secondary heart diseases such as congestive heart failure (CHF), acute CHF, chronic CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCMP), asymptomatic (latent) CHF, asymptomatic DCMP, chronic defect heart valve. Heart dysfunction can be associated with shock, expansion of the stomach, inversion of the intestines, and myocardial ischemia. Of these conditions, chronic heart valve disease (CHD) (also known as myxomatous valve degeneration) is one of the most common.

CPA is more common in female dogs than in males and usually affects the left atrioventricular or mitral valve, although the right atrioventricular or tricuspid valve is affected in about 30% of cases. The prevalence of CPA is much higher in small dogs, for example, dogs whose body weight is less than 20 kg, although larger dogs can also be affected. The cause of CPX is unknown.

The American College of Veterinary Therapeutic Medicine (ACVIM) published a consensus statement on CPA in 2009, which defines four stages for the functional classification of heart failure, namely:

- Grade I describes patients with asymptomatic heart disease;

- Grade II describes patients with heart disease, showing clinical signs only during intense physical activity;

- Grade III describes patients with heart disease, showing clinical signs during normal daily activities or light physical exertion; and

- Grade IV describes patients with heart disease showing severe clinical signs even at rest.

Consistent ACVIM recommendations for the treatment of CPC include the administration of a cardiotonic agent. ACVIM recommended the administration of pimobendan, a cardiotonic drug, twice a day for acute treatment in a hospital and long-term treatment at home of Class III CPX.

The agreed ACVIM guidelines also include the treatment of chronic class III CPX with furosemide, a diuretic, in addition to pimobendan treatment. The indicated diuretic is recommended for both acute and long-term treatment. For acute treatment of CPCS, a combination of furosemide and pimobendan is preferred.

Consistent ACVIM recommendations include long-term treatment of CPX with an angiotensin converting enzyme (ACE) inhibitor (ACE), such as enalapril. Evidence confirming the efficacy and safety of ACE inhibitors is less clear for acute treatment of class III CPX than for long-term treatment of CPC. In addition, ACE inhibitors are suitable for the treatment of hypertension.

The preferred consensus opinion of ACVIM for long-term treatment of class III CVD is to administer one or more of: pimobendan, furosemide and ACE inhibitors.

Given the significant problem associated with heart disease and / or hypertension, there is still a need to develop improved formulations of active agents suitable for treating such conditions.

SUMMARY OF THE INVENTION

According to a first aspect, there is provided a liquid composition comprising propylene glycol and an effective amount of a cardiotonic agent, an angiotensin converting enzyme inhibitor, or a combination of a cardiotonic agent and an angiotensin converting enzyme inhibitor.

According to a second aspect, there is provided a liquid composition comprising an effective amount of a cardiotonic agent and propylene glycol.

In accordance with a third aspect, there is provided a liquid composition comprising an effective amount of an angiotensin converting enzyme inhibitor and propylene glycol.

According to a fourth aspect, there is provided a liquid composition comprising propylene glycol and an effective amount of a combination of a cardiotonic agent and an angiotensin converting enzyme inhibitor.

The composition may contain one or more additional active agents, such as a diuretic or calcium channel blocker.

In accordance with a fifth aspect, there is provided a method of treating heart disease and / or hypertension, comprising administering a composition as defined above to a subject in need thereof.

The use of propylene glycol and an effective amount of a cardiotonic agent, an angiotensin converting enzyme inhibitor, or a combination of a cardiotonic agent and an angiotensin converting enzyme inhibitor for the preparation of a liquid composition for treating heart disease and / or hypertension are also proposed.

Also provided is a composition as defined above for use in the treatment of heart disease and / or hypertension.

The use of the composition as defined above for the treatment of heart disease and / or hypertension is also proposed.

Heart disease includes primary and secondary heart disease. Primary heart disease can be selected from the group consisting of congestive heart failure (CHF), acute CHF, chronic CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCMP), asymptomatic (latent) CHF, asymptomatic DCMP, and chronic heart valve disease or their combinations. Secondary heart disease can be selected from the group consisting of cardiovascular dysfunction and impaired renal perfusion during anesthesia, shock, expansion of the stomach, inversion of the intestines, myocardial ischemia and renal ischemia, or a combination thereof.

Hypertension is usually associated with activation of the renin-angiotensin-aldosterone system (RAAS). Disorders associated with hypertension include hyperadrenocorticism, hyperthyroidism, pheochromocytoma, primary hyperaldosteronism, diabetes mellitus, and kidney disease, or a combination thereof.

According to a sixth aspect, there is provided a method for preparing a composition as defined above, which comprises mixing an effective amount of a cardiotonic agent and / or an angiotensin converting enzyme inhibitor with propylene glycol.

According to a seventh aspect, there is provided a kit comprising a first composition containing an effective amount of a cardiotonic agent and a second composition containing an effective amount of an angiotensin converting enzyme inhibitor, said first and second compositions being separately, and at least one of the first and second compositions contains propylene glycol.

According to an eighth aspect, there is provided a kit comprising a first composition containing an effective amount of a cardiotonic agent or an angiotensin converting enzyme inhibitor, and a second composition containing an additional active agent, wherein said first and second compositions are separately, and at least one of the first and second formulations contains propylene glycol.

Brief Description of the Figures

FIG. 1 is a graph showing a comparison of plasma concentrations of pimobendan in dogs after oral administration of a test veterinary product IVP and a reference veterinary product RVP.

FIG. 2 is a graph showing a similar comparison, as in FIG. 1, in the case of a different IVP compared to a commercial veterinary product (CVP) containing pimobendan, from a separate in vivo study.

FIG. 3 is a graph showing a comparison of plasma pimobendan concentrations in dogs after oral administration of a liquid formulation containing pimobendan and propylene glycol and a liquid formulation containing pimobendan without propylene glycol.

FIG. 4 is a graph showing a comparison of plasma concentrations of pimobendan in dogs after oral administration of two test veterinary products containing a combination of pimobendan and an ACE inhibitor and a commercial veterinary product CVP containing pimobendan as the active ingredient.

FIG. 5 is a graph showing a comparison of plasma enalapril concentrations in dogs after oral administration of a test veterinary product (IVP) containing pimobendan and enalapril and a commercial veterinary product (CVP) containing enalapril without pimobendan.

FIG. 6 is a graph showing a comparison of plasma enalaprilate concentrations in dogs after oral administration of IVP and CVP from FIG. 5.

FIG. 7 is a graph showing plasma concentrations of enalapril and enalaprilate after oral administration of the IVP of FIG. 5 and 6, which demonstrates the conversion of enalapril pro drugs to active enalaprilat in vivo.

FIG. 8 is a graph showing a comparison of plasma concentrations of benazepril in case of IVP4 containing a combination of pimobendan and benazepril, IVP3 containing benazepril without pimobendan and a commercial veterinary product (CVP2) containing benazepril without pimobendan.

FIG. 9 is a graph showing a comparison of plasma concentrations of benzazeprilate in the case of IVP4, IVP3, and CVP2 described for FIG. 8.

FIG. 10 is a graph showing plasma concentrations of benazepril and benazeprilat after oral administration of IVP3, which demonstrates the conversion of a benazepril prodrug to active benazeprilat in vivo.

FIG. 11 is a graph showing plasma concentrations of benazepril and benazeprilat after oral administration of IVP4, which demonstrates the conversion of the benazepril prodrug to active benazeprilat in vivo.

Detailed Description - Liquid Composition

In one aspect, a liquid composition is provided comprising propylene glycol and an effective amount of a cardiotonic agent, an angiotensin converting enzyme inhibitor, or a combination of a cardiotonic agent and an angiotensin converting enzyme inhibitor.

The composition is suitable for oral or parenteral administration to a subject in need, such as a dog or cat, and can be used for acute or long-term treatment of heart disease and / or hypertension. Oral administration is generally preferred for long-term therapy, while parenteral administration may be preferred for acute treatment. Thus, the liquid composition may be in the form of a pharmaceutical composition for use in veterinary medicine or in humans.

In accordance with one aspect, a liquid composition is provided comprising an effective amount of a cardiotonic agent and propylene glycol.

An example of a cardiotonic agent is pimobendan. Prior to the present invention, pimobendan was available as a solid composition for oral administration or as an aqueous composition for injection. These formulations are often difficult to enter. This is especially problematic for the treatment of chronic conditions such as CPCS, since drug therapy is often necessary throughout the remainder of the animal’s life.

For example, administering tablets to a dog or cat is often difficult due to the subject's unwillingness to swallow the tablet. In addition, the implementation of drug therapy by injection, for example, intravenous, intramuscular or subcutaneous injection, is difficult for pet owners who may not have any medical preparation, and can lead to a number of possible complications. Moreover, subjects who find it difficult to administer doses may experience stress during treatment and, therefore, the management of clinically manifested heart disease will be less than optimal. In addition, if it is difficult for the animal to administer doses, the owners or carers will be reluctant to provide treatment and adherence to the treatment regimen and regimen will be low, which also leads to less than optimal control of heart disease.

It has been unexpectedly discovered that liquid formulations containing a cardiotonic agent and propylene glycol have unexpectedly preferred properties. In this regard, it was found that the liquid composition containing pimobendan and propylene glycol is a stable and bioavailable composition when administered orally.

Pimobendan is (RS) -6- [2- (4-methoxyphenyl) -1H-benzimidazol-5-yl] -5-methyl-4,5-dihydropyridazin-3 (2H) -one and has the following structure:

Pimobendan is a benzimidazole substituent that is extremely insoluble in water. For example, 1 g of pimobendan is dissolved in 10,000 ml of water. This solubility is known to be pH dependent, with solubility at pH 7 of 0.1 mg per 100 ml (or 1 g per 1,000,000 ml). This solubility is too low to produce a solution with an effective amount of a drug. In addition, while the pH of the stomach of the subject is generally low, for example, a pH of about 1 to 2 for dogs, the pH of the stomach of a particular subject can vary, for example, the pH of the stomach in dogs can vary from about pH 1 to about pH 8, which can be influenced by factors such as whether the pH was measured on an empty stomach or after eating. Thus, prior to the present invention, it was known that the solubility of pimobendan in the stomach increases with the addition of citric acid to the composition to be administered. Accordingly, in order to provide a bioavailable form of pimobendan, pimobendan solid compositions containing citric acid were obtained.

As an alternative, it has been shown that adding increasing concentrations of hydroxypropyl beta-cyclodextrin (HPβCD) to aqueous solutions of pimobendan can increase the solubility of pimobendan to concentrations from 0.5 to 1.5 mg / ml in an aqueous composition at pH greater than 5. However, at pH 3 to 5 addition of HPβCD does not effectively increase the solubility of pimobendan in water. Such aqueous formulations are suitable for intravenous (iv) and / or subcutaneous (s / c) administration of pimobendan.

Therefore, prior to the present invention, it was believed that additives for successful preparation of stable and bioavailable pimobendan formulations, such as citric acid or hydroxypropyl beta-cyclodextrin, were necessary because of the low and pH-dependent solubility of pimobendan in water.

As described herein, it has been found that pimobendan liquid formulations can be prepared which are stable and provide a source of easily and quickly systemically absorbable or bioavailable pimobendan, while they do not require the addition of citric acid or hydroxypropyl-beta-cyclodextrin.

Liquid formulations have advantages over solid formulations when administering drugs to animals. For example, in most cases, it is easier to administer the active agent to the animal in liquid form by quickly delivering a dose from, for example, a syringe or other dosing device to the animal’s mouth without chewing or in some cases swallowing the animal. In addition, compared to tablets and capsules that contain a fixed dose, the amount of pimobendan for administration can be easily adjusted according to the body weight of the subject by selecting the appropriate volume of liquid composition for administration.

The inventors of the present invention unexpectedly found that a stable solution of a cardiotonic agent such as pimobendan can be obtained using propylene glycol without citric acid or cyclodextrin. Such a liquid composition unexpectedly provides good solubility of pimobendan in aqueous solutions over the entire pH range in accordance with in vivo pH levels. The inventors of the present invention have also found that such liquid formulations provide a cardiotonic agent bioavailable upon oral administration.

Citric acid gives a taste that is unpleasant for animals such as dogs. Therefore, tablets containing citric acid have an unpleasant taste for dogs, which is often not satisfactorily masked by the use of taste improvers. Accordingly, the advantage of discovering that a stable pimobendan composition can be obtained using propylene glycol without citric acid is to provide formulations that have a more attractive taste for animals such as dogs or cats. This significantly increases the convenience of administering pimobendan to animals, and can also contribute to the long-term maintenance of treatment.

The solubility of pimobendan in the composition containing HPβCD in water at a pH of 3 to 5 is low. Such a composition may not be suitable for oral administration, since the solubility of pimobendan in water is not maintained over a wide pH range.

Accordingly, an advantage of discovering by the present inventors that a stable pimobendan composition can be obtained using propylene glycol without HPβCD is the preparation of formulations that are bioavailable upon oral administration and which may also be suitable for parenteral administration. This may help to administer the composition of pimobendan to subjects, and may also contribute to the long-term maintenance of the treatment of heart disease, for example, CHF or CPHC.

The liquid composition may consist of or contain a solution or emulsion. The solution contains one or more components dissolved in a liquid carrier. An emulsion contains a liquid suspended in another liquid, typically with an emulsifier. A microemulsion is a thermodynamically stable solution that is transparent upon visual inspection. For some microemulsions, one or more of the components may be suspended in a liquid carrier and have a particle size that is too small to be visible to the eye.

A cardiotonic agent can be any compound that is capable of exerting a positive inotropic effect and a vasodilating effect when administered to a subject in need thereof. For example, the cardiotonic agent may be pimobendan, levosimendan, amrinone, enoximon, milrinone, olprinone or springrinone. Typically, the cardiotonic agent may be pimobendan. As used herein, the term “cardiotonic agent” includes pimobendan, its pharmaceutically and / or veterinarily acceptable salts, derivatives, metabolites, stereoisomers or prodrugs.

The subject mentioned above may be a human or any animal in respect of which treatment with a cardiotonic agent may have a beneficial effect. The specified animal may be a mammal, usually a companion animal, for example, a dog, horse or cat, and may also include other types of mammals. As used herein, the term “animal” includes, but is not limited to, companion animals such as dogs, cats, guinea pigs, hamsters, horses, cattle, goats, sheep, and the like. Typically, the subject is a dog, horse or cat, most often a dog or cat. However, animals in need of such treatment may also include animals at the zoo, such as monkeys, elephants, giraffes, and other ungulates, bears, mice, and other small mammals.

In a preferred embodiment of the liquid formulation, the cardiotonic agent is pimobendan, its pharmaceutically or veterinarily acceptable salts, derivatives or metabolites.

In the case of pharmaceutically or veterinarily acceptable salts, these salts include, for example, inorganic salts such as chloride, sulfate, phosphate, diphosphate, bromide and / or nitrate salts. In addition, the compositions according to the present invention may also contain organic salts, such as, for example, malate, maleate, fumarate, tartrate, succinate, ethyl succinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfate, palmoate stearate, estolate, gluceptate or lactobionate salts. At the same time, the corresponding salts may contain pharmaceutically acceptable cations, such as, for example, sodium, potassium, calcium, aluminum, ammonium.

The cardiotonic agent may be present in amounts of from about 0.01 mass. % to about 50 mass. %, from about 0.01 mass. % to about 45 mass. %, from about 0.01 mass. % to about 40 mass. %, from about 0.01 mass. % to about 35 mass. %, from about 0.01 mass. % to about 30 mass. %, from about 0.01 mass. % to about 25 mass. %, from about 0.05 mass. % to about 50 mass. %, from about 0.05 mass. % to about 35 mass. %, from about 0.05 mass. % to about 25 mass. %, from about 0.1 mass. % to about 50 mass. %, from about 0.1 mass. % to about 35 mass. %, from about 0.1 to about 25 mass. %, from about 1 mass. % to about 50 mass. %, from about 1 mass. % to about 35 mass. %, from about 1 mass. % to about 25 mass. %, from about 0.01 mass. %) to about 20 mass. %, from 0.1 mass. % to about 50 mass. %, from about 1 mass. % to about 20 mass. %, from about 5 mass. % to about 20 mass. %, from about 5 mass. % to about 50 mass. %, from about 3 mass. % to about 25 mass. %, from about 3 mass. % to about 50 mass. % or from about 0.1 mass. % to about 5 mass. % of the total weight of the composition.

In some embodiments, the cardiotonic agent is present in an amount less than or equal to 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.3, 0.1, 0.05 or 0.01 mass. % of the total weight of the composition.

The composition also contains propylene glycol. Propylene glycol has the molecular formula C ₃ H ₆ (OH) ₂ .

The inventors of the present invention unexpectedly found that a liquid composition containing a cardiotonic agent and propylene glycol has a comparable, and in some cases greater bioavailability compared to the bioavailability of commercially available solid pimobendan solid formulations in dogs. In particular, as shown in the bioavailability studies described herein, unlike the solid commercially available pimobendan formulation, citric acid is not required for the liquid formulation of the present invention to exhibit effective oral bioavailability. The liquid formulation in the bioavailability studies described herein also does not contain cyclodextrin, such as hydroxypropyl beta-cyclodextrin.

The inventors have also found that a liquid composition containing pimobendan and propylene glycol more effectively provides bioavailable pimobendan after oral administration in a dog than a liquid composition containing pimobendan in the absence of propylene glycol, see, for example, Example 3 and FIG. 3.

Propylene glycol may be present in an amount of from about 0.05 mass. % to about 99.99 mass. %, from about 0.05 mass. % to about 99.9 mass. %, from about 0.05 to about 99 mass. %, from about 0.05 mass. % to about 97 wt. %, from about 0.05 mass. % to about 55 mass. %, from about 0.05 mass. % to about 50 mass. %, from about 0.05 mass. % to about 65 mass. %, from about 5 mass. % to about 99.99 mass. %, from about 10 mass. % to about 99.99 mass. %, from about 20 mass. % to about 99.99 mass. %, from about 5 mass. % to about 60 mass. %, from about 5 mass. % to about 50 mass. %, from about 10 mass. % to about 50 mass. % or at least 20 mass. % of the total weight of the composition. For example, propylene glycol may be present in an amount of at least 65, 60, 65, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.75, 0.5, 0.2, 0.1 or 0.05 mass. % of the total weight of the composition. Any amount of propylene glycol indicated herein can be used with any amount of a cardiotonic agent such as pimobendan indicated herein, provided that sufficient propylene glycol is used to solubilize the selected amount of cardiotonic agent.

The usual therapeutically effective target dose, in particular for the treatment of acute CHF, for example, pimobendan, as well as for any other therapeutic use described herein, is from about 0.05 to 1.0 mg pimobendan per kg of animal body weight per day typically from about 0.1 to 0.5 mg of pimobendan per kg of animal body weight per day, more often about 0.5 mg of pimobendan per kg of animal body weight per day. The daily dose, as a rule, is divided and administered in two equal doses, and in severe cases, three doses with approximately equal time intervals. The target concentration of pimobendan in the drug should be appropriately set at 5.0 mg / ml, which allows safe and equal volumes to be administered. For example, a dog with a body weight of 10 kg will accurately receive a dose of 0.5 ml containing 2.5 mg of pimobendan. A person skilled in the art will easily be able to adjust the amount of liquid composition depending on the mass and breed of the animal, and other factors that need to be taken into account, for example, existing conditions, the animal’s diet, a specific disease state and symptoms, etc. In addition, a person skilled in the art can easily determine the necessary dose for other cardiotonic agents depending on the disease state of the animal and the severity of the disease in accordance with the dose recommendations and practice.

Agreed ACVIM recommendations for long-term treatment of class III CVDs in dogs include combination treatment with pimobendan and an ACE inhibitor, such as enalapril, or another suitable ACE inhibitor, such as benazepril.

The authors of the present invention found that the composition containing ACE inhibitors and propylene glycol, provided bioavailable amounts of ACE inhibitors when administered orally in an animal, in particular in a dog after administration.

Accordingly, in one aspect, a liquid composition is provided comprising an effective amount of an angiotensin converting enzyme inhibitor and propylene glycol.

The renin-angiotensin-aldosterone system (RAAS) is complex and, when activated, leads to an increase in blood pressure. Angiotensin II is a powerful blood pressure regulator involved in RAAS, which causes constriction of blood vessels. Thus, lowering angiotensin II levels helps lower blood pressure by deactivating this aspect of RAAS. Angiotensin-converting enzyme (ACE) catalyzes the conversion of angiotensin I to angiotensin II. Therefore, it has been shown that ACE inhibition is an effective antihypertensive to lower blood pressure in humans and animals alike. Moreover, since activation of RAAS is one of the main causes of hypertension in animals, such as dogs and cats, ACE inhibitors are recommended as initial therapy when hypertension is detected in an animal.

In addition, lowering blood pressure is often useful for treating heart conditions, such as CHF and CPX.

Enalapril is an orally active prodrug of enalaprilate, an ACE inhibitor. Enalapril and enalaprilat have the following corresponding structures:

Benazepril is an orally active prodrug of benazeprilat, another ACE inhibitor. Benazepril and benazeprilat have the following corresponding structures:

Obviously, in the present description, a reference to an angiotensin converting enzyme inhibitor (ACE inhibitor) is a reference to either a prodrug of an ACE inhibitor or an active form of an ACE inhibitor, i.e. it includes enalapril and enalaprilat, benazepril and benazeprilat, their pharmaceutically and veterinarily acceptable salts, or a combination thereof. Other suitable ACE inhibitors include alacepril, cilazapril, delapril, fosinopril, imidapril, moexipril, spirapril, temocapril, tradolapril, zofenopril, captopril, ramipril, quinapril, perindopril, lisinopril and their pharmaceutically and veterinarily acceptable salts, or their pharmaceutically acceptable forms, their combination.

An angiotensin converting enzyme inhibitor may be present in amounts of from about 0.01 mass. % to about 50 mass. %, from about 0.01 mass. % to about 45 mass. %, from about 0.01 mass. % to about 40 mass. %, from about 0.01 mass. % to about 35 mass. %, from about 0.01 mass. % to about 30 mass. %, from about 0.01 mass. % to about 25 mass. %, from about 0.05 mass. % to about 50 mass. %, from about 0.05 mass. % to about 35 mass. %, from about 0.05 mass. % to about 25 mass. %, from about 0.1 mass. % to about 50 mass. %, from about 0.1 mass. % to about 35 mass. %, from about 0.1 to about 25 mass. %, from about 1 mass. % to about 50 mass. %, from about 1 mass. % to about 35 mass. %, from about 1 mass. % to about 25 mass. %, from about 0.01 mass. % to about 20 mass. %, from 0.1 mass. % to about 50 mass. %, from about 1 mass. % to about 20 mass. %, from about 5 mass. % to about 20 mass. %, from about 5 mass. % to about 50 mass. %, from about 3 mass. % to about 25 mass. %, from about 3 mass. % to about 50 mass. % or from about 0.1 mass. % to about 5 mass. % of the total weight of the composition.

In some embodiments, the angiotensin converting enzyme inhibitor is present in an amount less than or equal to 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32 , 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7 , 6, 5, 4, 3, 2, 1, 0.5, 0.3, 0.1, 0.05 or 0.01 mass. % of the total weight of the composition.

Propylene glycol may be present in an amount similar to that described above. Any amount of propylene glycol described above can be used with any amount of ACE inhibitors described above, provided that sufficient propylene glycol is used to solubilize the selected amount of ACE inhibitors.

The usual therapeutically effective target dose of ACE inhibitors, in particular for long-term treatment of class III CVDs, as well as for any other therapeutic use described herein, is from about 0.05 to 1.0 mg ACE inhibitors per kg of animal body weight per day, typically from about 0.1 to 0.5 mg and ACE per kg of animal body weight per day, usually about 0.5 mg ACE per kg of animal body weight per day. The daily dose is usually administered as a single dose after drinking water, but in severe cases it can be administered in two or three doses at approximately equal time intervals for one day. The target concentration of ACE inhibitors in the drug should be appropriately set at a level of from 5.0 to 10 mg / ml, which allows you to enter safe and equal volumes in accordance with the selected ACE inhibitors. For example, a dog with a body weight of 10 kg will accurately receive a dose of 0.5 ml containing 2.5 mg or 5.0 mg of ACE inhibitor. A person skilled in the art will easily be able to adjust the amount of liquid composition depending on the mass and breed of the animal, and other factors that need to be taken into account, for example, existing conditions, the animal’s diet, a specific disease state and symptoms, etc. In addition, a person skilled in the art will easily be able to determine the necessary dose for administering an effective amount of the particular ACE inhibitor administered, depending on the disease state of the animal and the severity of the disease in accordance with the dose recommendations and practice.

For example, the recommended dose for enalapril for long-term treatment of Class III CPX in dogs is approximately 0.5 mg / kg orally every 12 hours. The recommended dose range for enalapril is 0.25 to 0.5 mg / kg, orally every 12 hours or every 24 hours. Similarly, the recommended dose range for benazepril is 0.25 to 0.5 mg / kg, orally every 12 hours or every 24 hours.

Obviously, like the liquid composition of the cardiotonic agent described herein, administering an ACE inhibitor to an animal other than a human, such as a dog or cat, by delivery of the liquid composition is often easier than other forms of administration, for example, by tablet. In addition, prior to the present invention, there were no commercially available non-aqueous, orally available, ready-to-use liquid ACE inhibitors. To maintain chronic conditions in animals such as dogs or cats, ready-to-use liquid formulations available for oral administration are desirable.

As described herein, the present inventors have found that a composition containing a cardiotonic agent, an ACE inhibitor and propylene glycol provides plasma levels of an active cardiotonic agent and an ACE inhibitor within the published therapeutic range.

Accordingly, in one aspect, a liquid composition is provided comprising propylene glycol and an effective amount of a combination of a cardiotonic agent and an angiotensin converting enzyme inhibitor.

The preparation of a ready-to-use liquid composition containing a combination of a cardiotonic agent and an angiotensin converting enzyme inhibitor is preferred for the reasons described above with respect to the ease of administering doses of the active agent to the animal in the liquid composition compared to other types of compositions. In addition, since cardiotonic agents and angiotensin-converting enzyme inhibitors are often administered as a combination in the treatment of heart disease, this composition can contribute to adherence to the treatment regimen and regimen, and maintenance of treatment.

The combined composition contains propylene glycol, a cardiotonic agent and an angiotensin converting enzyme inhibitor in amounts similar to the amounts described above. One skilled in the art can readily determine the amounts of a cardiotonic agent and an angiotensin converting enzyme inhibitor for inclusion in a combination formulation based on the recommended dose for the particular agent selected. In addition, the amount of the combined composition for administration will be easily determined based on the concentrations of each active substance and can be modulated depending on the factors described above, such as the animal’s body weight, disease state and severity of the disease, etc.

The compositions described herein may additionally contain one or more pharmaceutically or veterinarily acceptable excipients. The excipient may be any pharmaceutically or veterinarily acceptable excipients for the liquid dosage form. Excipients that may be present in the composition include a surfactant, a thickening agent, flavor enhancer, preservative, solvent, or a combination thereof.

For example, the composition may contain a surfactant. Surfactants are compounds that contain both a hydrophilic and a hydrophobic region in one molecule, which allows them to reduce the surface tension between the aqueous and non-aqueous phases so that mixing can occur. The surfactant may be an anionic surfactant, a cationic surfactant, an ampholytic surfactant or a nonionic surfactant, or a combination of such surfactants may be used. Anionic surfactants include aluminum monostearate, calcium stearoyl lactylate, sodium cetostearyl sulfate, sodium cocoyl isethionate, sodium cocoyl sarcosinate, sodium lauroyl sulphate, sodium lauroyl isethionate or sodium cocoyl isethionate, sodium lauroyl sarcosinate, sodium stearate, sodium oleate, oleate sodium oleate. Cationic surfactants include tonsonium bromide. Ampholytic surfactants include aminocarboxylic acids, aminopropionic acid derivatives, imidazoline derivatives, and dodicin. Non-ionic surfactants include acetoglycerides, diethylene glycol esters, diethylene glycol ethers, ethylene glycol esters, glyceryl behenate, glycerol mono and diesters, glyceryl monocaprylocaprate, macro glyceryl monoglycerol, glyceryl monoglycerol, 6-glyceryl caprylocaprate, macrogol-20-glyceryl monostearate, macrogol-15-hydroxystearate, macrogollaurates, macrogol simple lauryl ethers, monomial macrogol tyl esters, macrogololeates, macrogol oleyl ethers, macrogol-40-sorbitolheptaoleate, macrogolstearates, macrogolglycerolcocoates, nonoxynols, octoxynols, oleyl oleate, palmitic acid, poloxylated, castrohydroxybenzene, castrohydroxybenzoic oils polysorbate 60, polysorbate 40, polysorbate 20, etc.), polyvinyl alcohol, propylene glycol caprylates, propylene glycol diacetate, propylene glycol laurates, propylene glycol monopalmitostearate, quillai, complex sorbitan esters, sucrose esters, triglyceryl diisostearate and tyloxapol.

Surfactant may be present in amounts of from about 1 mass. % to about 99 wt. %, from about 1 mass. % to about 90 mass. %, from about 1 mass. % to about 80 mass. %, from about 1 mass. % to about 60 mass. %, from about 1 mass. % to about 40 mass. %, from about 1 mass. % to about 30 mass. %, from about 1 mass. % to about 25 mass. %, from about 5 mass. % to about 99 wt. %, from about 5 mass. % to about 90 mass. %, from about 5 mass. % to about 80 mass. %, from about 5 mass. % to about 60 mass. %, from about 5 mass. % to about 40 mass. %, from about 5 mass. % to about 30 mass. %, from about 5 mass. % to about 25 mass. %, from about 20 mass. % to about 99 wt. %, from about 20 mass. % to about 90 mass. %, from about 20 mass. % to about 80 mass. %, from about 20 mass. % to about 60 mass. % or from about 20 mass. % to about 40 mass. % of the total weight of the composition.

For example, the composition may contain a viscosity modifier. The specified viscosity modifier may be any pharmaceutically or veterinarily acceptable substance that modifies the viscosity of the liquid composition to a suitable consistency for use. Thus, the viscosity modifier may be a thickener or a thinner. The viscosity modifier may be, for example, gum, agar, alginic acid, aluminum-magnesium silicate, aluminum monostearate, bentonite, carbomers, carmellose, carrageenan, cellulose, ceratonium, cetostearyl alcohol, cetyl alcohol, ethyl cellulose, gellanopara , hyetellose, hymellose, hyprolose, hypromellose, methyl cellulose, polyethylene oxide, polyvinyl acetate, polyvinyl alcohol, povidone, silicon dioxide, stearyl alcohol and tragacanth, or a combination thereof. Typically, the viscosity modifier may be polyethylene glycol, such as PEG300, polypropylene glycol, microcrystalline cellulose, polyvinylpyrrolidine or hydroxypropyl cellulose, or a combination thereof.

The viscosity modifier may be present in amounts of from about 0.05 mass. % to about 50 mass. %, from about 0.05 mass. % to about 30 mass. %, from about 0.05 mass. % to about 10 mass. %, from about 0.1 mass. % to about 50 mass. %, from about 0.1 mass. % to about 30 mass. %, from about 0.1 mass. % to about 10 mass. %, from about 1 mass. % to about 50 mass. %, from about 1 mass. % to about 30 mass. % or from about 1 mass. % to about 10 mass. % of the total weight of the composition.

The composition of the present invention may further comprise a flavor enhancer. The specified flavor enhancer may be any substance or mixture that enhances the taste of the composition for the subject in need. The flavor enhancer may be a sweetener. Thus, the flavor enhancer may include a sugar substitute or other flavoring, such as chicken or beef. For example, a flavor enhancer may be potassium acesulfame, alitam, aspartame, aspartame acesulfame, benzaldehyde, caramel, cyclamic acid, dibutyl sebacinate, erythritol, ethyl acetate, ethyl cinnamate, ethyl maltol, ethyl vanillin, maltolum neuromaldinum num , saccharin, saffron, stevioside, sucrose octaacetate, thaumatin, cocoa, tributylacetyl citrate, vanilla, vanillin, xylitol, dextrose, sucrose or glucose, or a combination thereof. Typically, the flavor enhancer may be selected from the group consisting of acesulfame potassium and stevioside, or a combination thereof.

The flavor enhancer may be present in amounts of from about 0.1 mass. % to about 40 mass. %, from 0.1 mass. % to about 20 mass. %, from about 5 mass. % to about 40 mass. % or from about 5 wt. % to about 20 mass. % of the total weight of the composition.

The composition of the present invention may also contain a preservative. The specified preservative may be an antioxidant, an antimicrobial agent, a free radical scavenger, or any other agent that extends the shelf life of the composition. For example, the preservative may be benzoic acid, sodium benzoate, sodium propionate, sorbic acid, benzyl alcohol, bronopol, chlorobutol, phenoxyethanol, o-phenoxyethanol, chlorhexidine salts, hydroxybenzoate derivatives, phenylmercury salts, thiomersal, chlorocresol, benzene, phenol, cresol, phenol , cetrimide, alpha-tocopherol, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene or sodium metabisulfite, or a combination thereof. Typically, the preservative may be benzyl alcohol, phenoxyethanol, o-phenylethanol or phenol, or a combination thereof. More often, the preservative may be benzyl alcohol.

The preservative may be present in the composition in amounts of from about 0.001 mass. % to 10 mass. %, from about 0.001 mass. % to about 1 mass. %, from about 0.01 mass. % to about 10 mass. % or from about 0.01 mass. % to about 1 mass. % of the total weight of the composition.

The composition of the present invention may also contain a solvent in addition to propylene glycol. For example, said solvent may be glycerol, ethanol, propanol, butanol, amyl acetate, amylene hydrate, butylene glycol, formalin glycerol, hexylene glycol, polyethylene glycol, for example, PEG300, glycofurol, pyrrolidone, propylene glycol diacetate, or vegetable oil such as canola olives, such as olive oils castor oil, peanut butter, etc., or a combination thereof. Typically, the solvent may be glycerol or PEG300.

The solvent may be present in the composition in amounts of from about 1 mass. % to about 99.94 mass. %, from about 1 mass. % to about 90 mass. %, from about 1 mass. % to about 75 mass. %, from about 1 mass. % to about 70 mass. %, from about 1 mass. % to about 65 mass. %, from about 1 mass. % to about 60 mass. %, from about 1% to about 50 mass. %, from about 7 mass. % to about 99.94 mass. %, from about 7 mass. % to about 90 mass. %, from about 7 mass. % to about 75 mass. %, from about 7 mass. % to about 70 mass. %, from about 7 mass. % to about 65 mass. %, from about 7 mass. % to about 60 mass. %, from about 7 mass. % to about 50 mass. %, from about 15 mass. % to about 99.94 mass. %, from about 15 mass. % to about 90 mass. %, from about 15 mass. % to about 75 mass. %, from about 15 mass. % to about 70 mass. %, from about 15 mass. % to about 65 mass. %, from about 15 mass. % to about 60 mass. % or from about 15 wt. % to about 50 mass. % of the total weight of the composition.

It will be apparent to those skilled in the art that an adjuvant, for example, a flavor enhancer, such as orange, lemon, or lime, may contain small amounts of citric acid. When such an excipient is included in the liquid composition described herein, the amount of citric acid is less than the amount necessary to provide a bioavailable amount of a cardiotonic agent, such as pimobendan, in an animal after oral administration. These formulations will contain citric acid in a ratio of pimobendan and citric acid of less than 1:10.

Accordingly, according to another aspect, there is provided an orally acceptable liquid composition comprising a cardiotonic agent such as pimobendan and not containing an acidic solubility enhancer such as citric acid. In one embodiment, the composition in accordance with this aspect contains citric acid in an amount of less than about 5, 4, 3, 2, 1, 0.5, 0.05, or 0.01 mass. % of the total mass of the composition, as a rule, does not contain at all.

In addition to auxiliary substances, the composition according to the present invention may also contain one or more additional active agents. As used herein, the term “active agent” refers to a compound that, after administration, provides a therapeutic effect in a subject, in other words, the active agent is a pharmaceutical or veterinary substance. Additional active agents that can be administered in conjunction with a cardiotonic agent, such as pimobendan, and / or an ACE inhibitor, such as, for example, enalapril or benazepril, for the treatment of heart disease, such as CHF, CVD, or other heart conditions discussed above, are known in the art and include a diuretic such as, for example, furosemide, spironolactone, chlortalidone or hydrochlorothiazide, or a combination thereof. Additional active agents that can be administered together with an ACE inhibitor for the treatment of hypertension include calcium channel blockers, such as, for example, amlodipine.

Additional active agent may be present in amounts of from about 0.01 mass. % to about 50 mass. %, from about 0.01 mass. % to about 45 mass. %, from about 0.01 mass. % to about 40 mass. %, from about 0.01 mass. % to about 35 mass. %, from about 0.01 mass. % to about 30 mass. %, from about 0.01 mass. % to about 25 mass. %, from about 0.05 mass. % to about 50 mass. %, from about 0.05 mass. % to about 35 mass. %, from about 0.05 mass. % to about 25 mass. %, from about 0.1 mass. % to about 50 mass. %, from about 0.1 mass. % to about 35 mass. %, from about 0.1 to about 25 mass. %, from about 1 mass. % to about 50 mass. %, from about 1 mass. % to about 35 mass. %, from about 1 mass. % to about 25 mass. %, from about 0.01 mass. % to about 20 mass. %, from 0.1 mass. % to about 50 mass. %, from about 1 mass. % to about 20 mass. %, from about 5 mass. % to about 20 mass. %, from about 5 mass. % to about 50 mass. %, from about 3 mass. % to about 25 mass. %, from about 3 mass. % to about 50 mass. % or from about 0.1 mass. % to about 5 mass. % of the total weight of the composition.

In some embodiments, the additional active agent is present in an amount less than or equal to 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32 , 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7 , 6, 5, 4, 3, 2, 1, 0.5, 0.3, 0.1, 0.05 or 0.01 mass. % of the total weight of the composition.

Obviously, any of the above amounts of the additional active agent can be used with any amount of cardiotonic and / or ACE inhibitors described above. Relative amounts of cardiotonic, ACE inhibitors and additional active agent can be selected in accordance with the relative recommended dose of each of them.

In one embodiment, the liquid composition may contain a diuretic such as furosemide, spironolactone, chlortalidone or hydrochlorothiazide, or a veterinary or pharmaceutically acceptable salt thereof.

Furosemide (sometimes called frusemide) is a diuretic of the following formula:

Furosemide is a loop diuretic, and its use for the treatment of hypertension and edema has been described. Furosemide is recommended for acute or prolonged treatment of Class III CPX in dogs. The agreed recommended dose of furosemide for acute class III CPX should correspond to the severity of the clinical signs and the response to the initial dose, for example, be a dose of from about 1 to about 4 mg / kg. For long-term treatment, higher doses are recommended, for example, greater than or equal to 6 mg / kg every 12 hours, or those that are required to maintain comfort in the patient, representing an animal.

Obviously, the reference to "diuretic" includes a reference to its pharmaceutically or veterinary acceptable salt, or its prodrug. Suitable diuretics include furosemide, hydrochlorothiazide, bumetanide, ethacrylic acid, torasemide, chlortiazide, chlortalidone, spironolactone, triamteren, amiloride, a pharmaceutically or veterinarily acceptable salt thereof, or a combination thereof.

When the liquid composition according to the present invention contains furosemide or another diuretic, one skilled in the art can easily adjust the dose of the liquid composition depending on the weight and breed of the animal, and other factors that need to be considered, for example, existing conditions, the diet of the animal, specific painful condition and symptoms, etc. In addition, a person skilled in the art can easily determine the required dose for a particular diuretic administered, for example, furosemide depending on the disease state of the animal and the severity of the disease in accordance with the dose recommendations and practice.

In accordance with another aspect, a liquid composition is provided comprising an active agent and propylene glycol, wherein said active agent is selected from the group consisting of a cardiotonic agent, an ACE inhibitor, a diuretic, and a combination thereof.

In one embodiment, the liquid composition in accordance with this aspect contains an active agent selected from the group consisting of pimobendan, enalapril, benazepril, furosemide, hydrochlorothiazide and their veterinary and pharmaceutically acceptable salts.

In some embodiments, the composition of the present invention is suitable for oral administration. The term “oral administration” means that the active agent is bioavailable after administration of the composition to a subject in need thereof by mouth. For formulations of the present invention containing a cardiotonic agent, after oral administration of an amount of the composition, an effective amount of the cardiotonic agent is bioavailable and is present in therapeutic concentrations in the plasma of the animal patient. For compositions according to the present invention containing ACE inhibitors, after oral administration, an effective amount of the active form of ACE inhibitors is bioavailable and is present in therapeutic concentrations in the plasma of the animal patient. Included is absorption through the mucous membrane of the oral cavity or cheek, the gastrointestinal tract, or any other route available for absorption of the drug when administered through the mouth.

Preferably, the liquid compositions of the present invention form a clear solution when added to water over the entire pH range, for example, from about 1 to about 9. For example, the liquid composition forms a clear aqueous solution when added to water at a pH of from about 1 to about 2, from about 6 to about 8, or from about 8 to about 9. These solutions mimic the pH conditions in various biological environments, for example, a pH of 8 to 9 is designed to simulate the pH of the oral cavity, a neutral pH with a pH value of from about 6 to 8 mimics that small intestine, and a pH of about 1 to 2 mimics the stomach. When the liquid composition forms a clear solution with water adjusted to each of these pH ranges, this means that pimobendan will remain in solution and that it may be bioavailable after oral administration to a subject in need thereof.

In some embodiments, the composition may be in the form of a sterile aqueous or oily solution, emulsion or suspension for injection. This suspension can be obtained in accordance with methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injection or suspension for injection in a non-toxic parenterally acceptable diluent or solvent, for example, in a mixture with N-methylpyrrolidone, with additional propylene glycol, or may be suitable without any additional additive. Among the acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectable formulations. Compositions for injection can be administered by bolus injection, intravenous (iv), intramuscular (iv) and / or subcutaneous (s / c) route.

Thus, in General, the liquid composition can be entered separately or in the form of a solution, emulsion or suspension. Thus, the liquid composition can be administered directly or, alternatively, can be diluted with a suitable carrier or diluents. For example, carriers or diluents may be water, glycerin, alkyl benzoate, beeswax, calcium sulfate, candelilla wax, cellulose, cetostearyl alcohol, cetyl alcohol, cetyl esters, cholesterol, coconut oil, cottonseed oil, creatinine, dextrates, dimethyl sulfide waxes, erythritol, ethyl oleate, glyceryl stearates, solid fat, paraffin wax, isopropyl myristate, isopropyl palmitate, macrogol monomethyl ethers, liquid paraffin, microcrystalline wax, myristyl alcohol, oleins acid, oleyl alcohol, palm oil, polydextrose, shea butter, silicones, soft paraffin, squalane, stearyl alcohol, cocoa, wool fat alcohol, wool fat and vegetable fatty oils, or a combination thereof.

Solutions and suspensions will typically be aqueous, for example, obtained only from water (e.g., sterile or pyrogen-free water) or water and a physiologically acceptable co-solvent (e.g., ethanol or polyethylene glycols such as PEG 400).

Such solutions or suspensions may additionally contain other auxiliary substances, for example, preservatives (such as benzalkonium chloride), solubilizing agents / surfactants, such as polysorbates (e.g. Tween 80, Span 80, benzalkonium chloride), buffering agents, agents, isotonicity regulators (e.g. sodium chloride), absorption enhancers and viscosity enhancers. Suspensions may further contain suspending agents (e.g., microcrystalline cellulose and sodium carboxymethyl cellulose).

If necessary, formulations suitable for providing sustained release of the active compound can be used.

The composition of the present invention can also be administered rectally. In these embodiments, the composition is administered into the rectum of a subject, and it may be in the form of a solution or suspension described above.

The liquid composition may be presented for use in the form of veterinary compositions, which can be obtained, for example, by methods conventional in the art. Examples of such veterinary compositions include compositions suitable for:

(a) oral administration, external use, for example, liquid dosage forms for oral administration (eg, aqueous or non-aqueous solutions or suspensions); liquid-filled capsules or boluses; powders, tablets containing granules or spheres containing the liquid composition described herein and can, for example, be used in admixture with food; pastes for application in the buccal cavity or on the tongue;

(b) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection, for example, in the form of a sterile solution or suspension;

(c) topical application; or

(d) administration rectally or intravaginally.

To facilitate combination therapy, the formulations defined above may be presented as part of a kit containing combinations of active agents.

Accordingly, according to one aspect, there is provided a kit comprising a first composition containing an effective amount of a cardiotonic agent and a second composition containing an effective amount of an angiotensin converting enzyme inhibitor, wherein said first and second compositions are contained separately, and at least one of the first and second compositions contains propylene glycol.

In accordance with another aspect, there is provided a kit comprising a first composition containing an effective amount of a cardiotonic agent or an angiotensin converting enzyme inhibitor, and a second composition containing an additional active agent, wherein said first and second compositions are contained separately, and at least one of the first and second formulations contains propylene glycol.

The cardiotonic agent and / or angiotensin converting enzyme inhibitor of the kits defined above may be any suitable cardiotonic agent or angiotensin converting enzyme inhibitor described herein. In one embodiment, the cardiotonic agent is pimobendan or a pharmaceutically or veterinarily acceptable salt thereof. In another embodiment, the angiotensin converting enzyme inhibitor is selected from the group consisting of enalapril, benazepril, pharmaceutically or veterinarily acceptable salts thereof, or a combination thereof.

The first and second compounds can be kept separately, each in a container. The indicated capacity may be suitable both for storage and for dosing the composition. Containers suitable for storage include, for example, blister packs, vials, ampoules, and the like. When such a container is used, the kit may further comprise a metering device, such as a syringe or a vessel with a volume label. Containers suitable for both storing and dispensing liquid formulations include, for example, a syringe, a volume labeled vessel, a sponge soaked in a liquid composition, and the like.

In some embodiments, the kit is suitable for administering the first and second formulations separately, sequentially, or simultaneously. Separate, sequential or simultaneous administration includes administration in different ways, for example, the first composition can be administered orally, and the second composition can be administered parenterally. In addition, separate and sequential administration includes the introduction of the first and second compositions in the same or different ways at different times, for example, with an interval of up to 6 hours, usually within about 2 hours one after the other.

In some embodiments, both the first and second formulations contain propylene glycol. In these embodiments, the first and second formulations may be combined prior to administration.

In one embodiment, the kit contains an additional composition containing an effective amount of an additional active agent. Typically, this composition is a liquid composition.

Said additional active agent may be a diuretic, for example, any of the suitable diuretics described above, including furosemide, chlortalidone, hydrochlorothiazide and their pharmaceutically or veterinarily acceptable salts, or a combination thereof, or may include the calcium channel blocker described above. Alternatively, if the kit already contains a diuretic, the additional active agent may be any of a cardiotonic agent, an angiotensin converting enzyme inhibitor or calcium channel blocker, whereby the kit contains a combination of a cardiotonic agent, an angiotensin converting enzyme inhibitor and a diuretic.

In another embodiment, the kit contains instructions for use.

Way

The liquid composition can be obtained by mixing with or without heating an effective amount of a cardiotonic agent and / or an angiotensin converting enzyme inhibitor with propylene glycol, and then by gradually adding any of the desired auxiliary substances or additional active agents mentioned above, if necessary.

Accordingly, according to one aspect of the present invention, there is provided a method for preparing a liquid composition comprising an effective amount of a cardiotonic agent, an angiotensin converting enzyme inhibitor or a combination of a cardiotonic agent and an angiotensin converting enzyme inhibitor, and propylene glycol comprising mixing an effective amount of a cardiotonic agent or an angiotensin converting enzyme inhibitor.

In one embodiment, the method further comprises sequentially adding one or more of the following excipients: a surfactant, viscosity modifier, flavor enhancer, preservative and solvent, or a combination thereof.

For example, the following protocol can be used to obtain a liquid composition containing:

Cardiotonic 0.25 g Propylene glycol 23 ml Preservative 0.05 ml Viscosity modifier 10 ml Flavor enhancer 0.2 g Surface-active substance 0.3 ml Solvent up to 50 ml

Stage 1: the cardiotonic agent is dissolved in propylene glycol (15 ml) when heated to about 65 ° C.

Stage 2: add solvent (5 ml) with stirring.

Stage 3: add a preservative with stirring.

Stage 4: add viscosity modifier with stirring.

Stage 5: the taste enhancer is dissolved in a separate vessel in propylene glycol (5 ml) with stirring.

Stage 6: the solution obtained in stage 5 is transferred to the bulk solution obtained in stage 4 with stirring.

Stage 7: Surfactant is dispersed and dissolved in a separate vessel in propylene glycol (3 ml) and solvent (3 ml). The solution is heated to about 65 ° C. before being added to the bulk solution.

Stage 8: the solution obtained in stage 6 is combined with bulk solution. Mix to obtain a clear solution. Allow to cool.

Step 9: Add the solvent to the final batch volume.

In embodiments of liquid formulations containing active agents other than a cardiotonic agent, including for liquid formulations containing a combination of a cardiotonic agent and another active agent, the method described above includes the additional step of dissolving the active agent in propylene glycol with or without heating with stirring as needed. Adding an additional active agent will often be carried out simultaneously or immediately after the 1st step described above.

For embodiments comprising an angiotensin converting enzyme inhibitor (ACE inhibitor) and propylene glycol, the cardiotonic agent is replaced with an ACE inhibitor in a method similar to that described above.

Application methods

The composition can be used to treat diseases in which cardiotonic, hypotensive, anti-inflammatory and anti-thrombotic substances have a useful therapeutic effect. Such diseases include heart disease and hypertension.

Heart disease includes primary and secondary heart disease. Primary heart disease includes, for example, congestive heart failure (CHF), acute CHF, chronic CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCMP), asymptomatic (latent) CHF, asymptomatic DCMP, and chronic heart valve disease, or a combination thereof. Secondary heart disease includes, for example, dysfunction of the cardiovascular system and impaired renal perfusion during anesthesia, shock, expansion of the stomach, inversion of the intestines, myocardial ischemia and renal ischemia, or a combination thereof.

Accordingly, in one embodiment, a method for treating primary or secondary heart disease is provided, comprising administering a composition as defined above to a subject in need thereof.

Hypertension is usually associated with activation of the renin-angiotensin-aldosterone system (RAAS) described above. Disorders associated with hypertension include hyperadrenocorticism, hyperthyroidism, pheochromocytoma, primary hyperaldosteronism, diabetes mellitus, and kidney disease, or a combination thereof.

Accordingly, in one embodiment, a method for treating a disease or disorder associated with activation of the renin-angiotensin-aldosterone system (RAAS) is provided.

The use of propylene glycol and an effective amount of a cardiotonic agent, an angiotensin converting enzyme inhibitor, or a combination of a cardiotonic agent and an angiotensin converting enzyme inhibitor for the preparation of a liquid composition for treating heart disease and / or hypertension are also proposed.

Also provided is a liquid formulation containing propylene glycol and an effective amount of a cardiotonic agent, an angiotensin converting enzyme inhibitor, or a combination of a cardiotonic agent and an angiotensin converting enzyme inhibitor, for use in the treatment of heart disease and / or hypertension.

It is also proposed the use of a liquid composition containing propylene glycol and an effective amount of a cardiotonic agent, an angiotensin converting enzyme inhibitor, or a combination of a cardiotonic agent and an angiotensin converting enzyme inhibitor, for treating heart disease and / or hypertension.

In one embodiment, the primary heart disease is selected from the group consisting of congestive heart failure (CHF), acute CHF, chronic CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCMP), asymptomatic (latent) CHF, asymptomatic DCMP and chronic defect heart valves or combinations thereof.

In one embodiment, the secondary heart disease is selected from the group consisting of dysfunction of the cardiovascular system and decreased renal perfusion during anesthesia, shock, expansion of the stomach, inversion of the intestines, myocardial ischemia and renal ischemia, or a combination thereof.

In some embodiments, the subject is a companion animal, such as a dog or cat.

In some embodiments, the administration is oral administration. Whereas in other embodiments, the administration is parenteral administration.

As is obvious to a person skilled in the art, an effective amount of an active agent, such as a cardiotonic, an ACE inhibitor or diuretic, will depend on various factors, including the activity of the particular active agent selected, the body weight of the subject in need of treatment, and the type and severity of the condition, which is being treated. One skilled in the art will be able to easily determine the effective amount of an active agent, such as a cardiotonic, an ACE inhibitor or diuretic, for administration to a subject in need of treatment, and based on this effective amount, determine the amount of the composition of the present invention for administration.

As described above, a typical therapeutically effective amount of pimobendan is from about 0.2 to 1.0 mg pimobendan per kg of animal body weight and the use is usually from about 0.3 to 0.6 mg pimobendan per kg of animal body weight and use , more often, approximately 0.5 mg pimobendan per kg body weight of the animal. Typically, two doses are administered per day, each dose representing half of the effective amounts indicated above. In some cases, a third dose may be administered. Slow absorption liquid pimobendan formulations may be suitable for once daily administration.

For example, a therapeutically effective amount for treating CHF is from about 0.2 to about 1.0 mg of pimobendan per kg of animal body weight per day, preferably from about 0.3 to about 0.6 mg of pimobendan per kg of animal body weight, more preferably approximately 0.5 mg pimobendan per kg body weight of the animal. Typically, two doses are administered per day, one dose in the morning, and the other after about 12 hours. Such treatment is also preferable in case of maintaining the function of the cardiovascular system and / or renal perfusion during anesthesia, shock, expansion of the stomach or inversion of the intestines, for example, as a result of surgery, especially surgery on the gastrointestinal tract, as well as trauma.

Conventional therapeutically effective amounts of ACE inhibitors of enalapril and benazepril are described above. Also described above is a conventional therapeutically effective amount of furosemide.

In general, the term “treatment” means exposing a subject, tissue or cell to a desired pharmacological and / or physiological effect and includes: (a) suppressing the disease, i.e. cessation of its development or further development; (b) weakening or alleviating the manifestations of the disease, i.e. achievement of remission; (c) reducing the incidence of the disease; or (d) preventing the disease in a subject, tissue or cell susceptible to the disease or at risk of its occurrence, but in which it has not yet been diagnosed, using a protective pharmacological and / or physiological effect so that the disease does not develop or does not occur in the specified subject, tissue or cell.

The following is a detailed link to specific embodiments of the present invention. Although the present invention has been described with respect to these specific embodiments, it is obvious that the present invention is not limited to such specific embodiments. On the contrary, it includes alternatives, modifications, substitutions, variations and equivalents within the essence and scope of the present invention defined by the attached claims.

Examples

Example 1: pimobendan solubility studies

Each composition was prepared by dissolving pimobendan in propylene glycol or another solvent, as described in Tables 1 to 4, and then gradually adding the remaining components while stirring the pimobendan and solvent with a magnetic stirrer. After obtaining each test composition, one ml sample was taken with a disposable pipette or syringe and added to 100 ml of water with a pH of 1-2, 7 or 9. Acidic water was obtained by adding hydrochloric acid to distilled water, controlling the pH with an electronic pH meter to achieve the desired pH. Alkaline water was obtained by adding sodium hydroxide to distilled water, monitoring the change in pH with a pH meter, and stopping the addition of NaOH when the desired pH was reached.

After adding and thoroughly mixing 1 ml of each test composition in 100 ml samples of three waters with different pH values, the appearance of each mixture was noted and recorded, and summarized in tables 1 to 4.

Example 2: bioavailability study

Six adult healthy dogs were selected for inclusion in the study. All dogs underwent a general physical examination (GPE), including determination of body weight before the start of the study. Dogs with cardiovascular disease evident in GPE were not included in the study.

There is evidence that the bioavailability of orally administered pimobendan is significantly reduced when administered with food or shortly after it. Therefore, food was refused at least 4 hours before treatment and for 1 hour after treatment. With the exception of day 0, dogs were fed commercial dry dog food to a maintenance level. Dogs always had access to fresh water.

Treatment assignment for each dog / group was masked for the laboratory. Treatment groups were not masked for administration staff.

Two different formulations were evaluated: the test veterinary product or IV p-pimobendan 5 mg / ml, the liquid composition (described in detail below) and the reference veterinary product or RVP - Vetmedin® (1.25, 2.5 and 5 mg), capsules (Boehringer Ingelheim )

Medicines were administered to each dog once every 0 day. Blood samples were taken at predetermined intervals (table 5) and analyzed.

IVP, liquid composition:

Pimobendan 0.5 g Propylene glycol 23 ml PEG 300 10 ml PVP 0.3 g Sufficient glycerin 50 ml

Animal studies were treated in accordance with the scheme shown in table 5. Individual doses were calculated in accordance with the body weight of the dog, fixed in the period immediately before the study.

The recommended dose of Vetmedin® in a dog is 0.2-0.6 mg / kg. A preferred daily dose is 0.5 mg / kg body weight. The dose should be divided into two doses at approximately 12-hour intervals. Each dose should be administered approximately one hour before feeding (Boehringer Ingelheim approved by the Australian Pesticides and Veterinary Medicines Authority, APVMA).

In this example, dogs were given once half the recommended total daily dose - i.e. 0.25 mg pimobendan / kg body weight.

Since capsule presentation is a limiting factor for the RVP dose in this example, all doses were rounded to the nearest multiple of 1.25 mg pimobendan per dog, which corresponded to the lowest capsule dosage available. A combination of capsule sizes was used to provide the most accurate dose of pimobendan for each dog, if necessary.

The dose for IVP was based on the equivalent dose in capsules for dog body weight.

IVP and RVP were administered orally.

Oral administration of IVP included the necessary dose in the syringe. A syringe was injected into the dog's mouth in a lip adhesion and the dose was placed on the back of the tongue. The dog's mouth was kept closed, and his head was thrown back a bit to ensure that the entire amount of the administered product was swallowed.

RVP capsules were placed on the root of the tongue in the back of the oral cavity and the dog's mouth was kept closed and his head was slightly thrown back to allow the capsule to be swallowed.

Each dog was closely monitored after treatment to ensure no burping or other extraction of IVP and RVP.

Dogs were not allowed to eat during the night, and morning feeding was delayed up to 1 hour after dosing. The treatment was carried out as close as possible to 8 in the morning.

Following oral administration to 3 dogs in each group, at a dose level of 0.25 mg pimobendan / kg body weight, the following plasma concentrations (ng / ml) of pimobendan were observed.

Plasma samples were analyzed using an approved analytical method based on separation and quantification using ultra high performance liquid chromatography and tandem mass spectrometry. Quantification data are given in ng / ml in tabular and graphical form. All but one dog exhibited typical absorption and excretion characteristics, but absorption for both products varied.

The data show that pimobendan is rapidly absorbed after IVP administration, and pimobendan remains in the circulatory system at concentrations exceeding the lower limit of quantification (LLOQ) for more than four hours. Based on the pharmacokinetic data obtained for dogs that were given an oral solution, it is obvious that absorption is independent of the presence of citric acid when the active component is present in the solution.

The observed C _max for the IVP treatment group had an average of approximately 13 ng / ml, and T _max was observed after either 1 or 2 hours. This demonstrates that pimobendan solution is rapidly absorbed at a faster rate and to a greater extent than described in the product information for Vetmedin.

Discussion

The task of the analytical component of this example was to determine the concentration of pimobendan in plasma in dogs obtained from six adult dogs, which were administered either IVP (oral solution) or RVP (Vetmedin® capsule). These data were necessary to determine the similarities or differences between the compositions of IVP and RVP in terms of the rate of absorption of pimobendan in the gastrointestinal tract, and the critical parameters C _max , T _max and AUC.

Pimobendan appears to be rapidly absorbed upon delivery orally in solution. The concentrations of pimobendan in the samples obtained 15 minutes after administration averaged 4.0 ng / ml (IVP) compared with 1.9 ng / ml (RVP). These results indicate that dissolved pimobendan is bioavailable almost immediately compared to the solid active component delivered in a capsule. In addition, the rapid absorption of the solution shows that to facilitate the absorption of the drug does not require a very unpleasant taste of the amount of citric acid.

The oral solution exhibits broader absorption characteristics; characterized by slightly lower C _max , slightly larger T _max and slightly higher AUC than RVP based on the data of three dogs examined in each group. Excretion rates are comparable between groups, but a study of the data 3 and 4 hours after treatment shows that the average concentrations of pimobendan in the IVP group are significantly higher than the average values in the RVP group. The solution, on average, made it possible to achieve a higher total systemic concentration of pimobendan for a longer period. This could translate into an enhanced therapeutic effect for dogs receiving this solution.

findings

This program included analysis of forty-eight dog plasma samples for pimobendan. Samples were characteristic of six dogs, every three of which were treated with either IVP (solution) or RVP (Vetmedin® capsule). Plasma samples were taken at indicated times after administration of the product.

An LCMS / MS analysis was developed and validated, and he could determine pimobendan in plasma in the range of 0.5-50 ng / ml.

Analysis of the data shows that oral administration of IVP can produce plasma concentrations of pimobendan in treated dogs, which are probably therapeutic.

Obvious is the rapid absorption of pimobendan after administration of a solution for oral administration. The data obtained suggest that in the phase of excretion, the systemic concentration of pimobendan from the oral solution is slightly higher and remains a little longer than in the case of RVP.

Example 3: bioavailability study

The study included 24 healthy adult beagles of both sexes, including neutered animals, weighing 11.3-21.7 kg from the age of 1 year, 9 months to 5 years. Dogs for the study were clinically examined and body weight was determined at -2 days. Dogs were ranked in descending order of body weight and sequentially combined into 3 blocks of 8 animals. The animals within each block were randomly distributed (by “pulling out of the hat”) into 8 treatment groups (1-8) so that each group had a similar range of body weight.

Test and Control Products

- Research Veterinary Products (IVP)

IVP1:

Pimobendan 0.25 g Propylene glycol 23 ml PEG 300 10 ml PVP 0.3 g Stevioside 90%, powder 0.1 g Acesulfame Potassium 0.1 g Benzyl alcohol 0.05 ml Glycerol up to 50 ml

IVP2:

Pimobendan 0.25 g PEG 300 10 g Stevioside 90%, powder 0.30 g Glycerol 6.0 g Polyvinylpyrrolidone (PVP) K90 0.3 g Benzyl alcohol 0.05 g Glycerol up to 50 ml

IVP3:

Benazepril hydrochloride 0.25 g Propylene glycol 23 ml PEG 300 10 ml PVP 0.3 g Stevioside 90%, powder 0.1 g Acesulfame Potassium 0.1 g Benzyl alcohol 0.05 ml Glycerol up to 50 ml

IVP4:

Pimobendan 0.25 g Benazepril hydrochloride 0.25 g Propylene glycol 23 ml PEG 300 10 ml PVP 0.3 g Stevioside 90%, powder 0.1 g Acesulfame Potassium 0.1 g Benzyl alcohol 0.05 ml Glycerol up to 50 ml

IVP 5:

Pimobendan 0.25 g Enalapril maleate 0.25 g Propylene glycol 23 ml PEG 300 10 ml PVP 0.3 g Stevioside 90%, powder 0.1 g Acesulfame Potassium 0.1 g Benzyl alcohol 0.05 ml Glycerol up to 50 ml

IVP 1 was obtained in accordance with the following protocol:

Stage 1: pimobendan was dissolved in propylene glycol (15 ml) when heated to about 65 ° C.

Stage 2: glycerol (5 ml) was added with stirring.

Stage 3: benzyl alcohol was added with stirring.

Stage 4: polyethylene glycol 300 was added with stirring.

Stage 5: Stevioside 90%, powder and acesulfame potassium in propylene glycol (5 ml) were dissolved in a separate vessel with stirring.

Stage 6: the solution obtained in stage 5 was transferred to bulk solution obtained in stage 4 with stirring.

Stage 7: polyvinylpyrrolidone K90 powder was dispersed and dissolved in a separate vessel in propylene glycol (3 ml) and glycerin (3 ml). The solution was heated to about 65 ° C. before being added to the bulk solution.

Stage 8: the solution obtained in stage 6 was combined with bulk solution. Mixed until a clear solution was obtained. Allowed to cool.

Step 9: Glycerin was added to the final batch volume.

IVP 2 was obtained in accordance with the following protocol:

Stage 1: pimobendan was dissolved in PEG300 at 65 ° C (approximately 30 minutes).

Stage 2: 90% stevioside was added to the mixture, the powder was dissolved.

Stage 3: glycerol (6.0 g) and polyvinylpyrrolidone (PVP) K90 (at 65 ° C) were combined in a separate vessel.

Stage 4: the mixture obtained in stage 3 was added to the dissolved pimobendan.

Stage 5: benzyl alcohol was added.

6th stage: brought up to 50 ml of glycerin. Well mixed.

IVP 3, 4 and 5 were obtained in accordance with a similar procedure described for IVP1, replacing, if necessary, the ingredients listed above.

- Control Veterinary Products (CVP)

Treatment and sampling

This example describes a pharmacokinetic study using a single period, conducted in dogs that were administered various cardiovascular agents. Pimobendan concentrations; benazepril and its active metabolite benazeprilat; enalapril and its active metabolite enalaprilat was determined in plasma samples obtained from test subjects, in the hours after administration of the compounds discussed above.

Dogs were not fed at approximately 0730 per day before treatment, which was carried out at 0930 (0 day) or 1000 (1 day) and which consisted of a single dose of IVP or RVP given orally to dogs at 2-minute intervals. Animal studies in treatment groups 1, 2, 4, and 6 were treated once every 0 day; in groups 3, 5, 7 and 8 - once every 1 day. Treatment group 1 was dosed with a 0.5% pimobendan solution (IVP1). Treatment group 2 was administered a 0.5% pimobendan solution (IVP2) solution. Treatment group 3 was administered a dose of 0.5% benazepril solution (IVP3). Treatment group 4 was dosed with a solution of pimobendan 0.5% and benazepril 0.5% (IVP4). Treatment group 5 was administered a dose of a solution of pimobendan 0.5% and enalapril 1.0% (IVP5). Treatment group 6 was administered a capsule containing pimobendan (CVP1). Treatment group 7 was administered a tablet containing benzazepril hydrochloride (CVP2). Treatment group 8 was administered a tablet containing enalapril maleate (CVP3). Immediately after administration of the tablet or capsule, each dog was given a small amount of water (5-10 ml) with a syringe to ensure that the tablets enter the stomach and there is no possible blockage in the “dry” esophagus. Liquid formulations were administered using 1.0 ml syringes. Water was available without restriction. Dogs were kept one in the pens for 3 hours after treatment, then 3 dogs in the pen were placed in treatment groups. Eat not given for at least 4 hours after treatment.

Blood samples were taken before treatment on day 2 and after 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours and 24 hours after treatment. Blood samples (approximately 5 ml) were collected from dogs by venipuncture of the head or jugular veins using new sterile needles and syringes with an eccentric Luer tip, and they were directly injected into a single 8 ml Vacuette® system containing a lithium heparin and gel separator. Samples were centrifuged and plasma was collected using new disposable plastic pipettes.

Plasma pimobendan concentrations were determined using an approved analytical method based on instrumental determination using ultra-high performance liquid chromatography-tandem mass spectrometry. Sample preparation included a deproteinization step before instrumental determination.

Benazepril, benazeprilat, enalapril and enalaprilat were determined using an analytical method based on instrumental determination using ultra-high performance liquid chromatography-tandem mass spectrometry. Lower detection limits were achieved using solid phase extraction for sample preparation.

To quantify the analyte, calibration graphs corresponding to the matrix obtained using the ratio of analyte to deuterated internal standards were used. Correlation coefficients of calibration plots exceeded 0.99 for quantitative analyzes. The lower limits of quantitation (LLOQ) for pimobendan, benazepril, benazeprilat, enalapril and enalaprilat were determined to be 0.2 ng / ml, which was considered sufficient for this study.

results

Discussion

- Pharmacokinetics (FC) of pimobendan

Groups 1, 2, 4, 5, and 6 were administered compositions containing pimobendan, i.e. IVP 1, 2, 4, and 5, and CVP1, respectively. Pimobendan was administered to all animals in groups 1, 2, 4, 5, and 6 at a target dose level of 0.25 mg / kg.

All treatment groups showed bioavailability of pimobendan after administration. IVP 1 containing pimobendan and propylene glycol showed a higher AUC than the commercial veterinary product, Vetmedin, a solid composition containing pimobendan and citric acid (FIG. 2). These results showed a reduced WPC for Vetmedin compared to the earlier study discussed in Example 2 above, probably due to natural biological variation.

IVP1, i.e. containing pimobendan and propylene glycol, also showed a greater AUC than IVP 2, i.e. containing pimobendan and not containing propylene glycol. IVP 2 contains both PEG 300 and glycerin, and these results suggest that propylene glycol provides more effective bioavailability of pimobendan after oral administration than a liquid composition containing solvents capable of solubilizing pimobendan, which are structurally similar to propylene glycol, i.e. PEG300 and glycerin (Fig. 3).

IVP 4 and 5 both contain a combination of pimobendan and ACE inhibitors. It was shown that both of them provide AUC within the therapeutic range and greater than CVP1 (Fig. 4). However, IVP 4 and 5 showed a lower AUC than IVP1, suggesting that the presence of ACE inhibitors may affect the bioabsorption of pimobendan. However, as mentioned above, PPC, Cmax and Tmax pimobendan, measured after oral administration of IVP 4 and 5, are suitable for use in therapy in the methods described herein. In addition, the increased effectiveness of propylene glycol compared to other solvents, such as PEG300 and glycerin, is especially useful in these combination formulations to provide the desired plasma pimobendan concentrations after oral administration.

- FC Enalapril

Enalapril is a prodrug of the active agent enalaprilat available for oral administration. Plasma concentrations of enalapril and enalaprilat were measured. Enalaprilat concentration is related to the effectiveness of a given ACE inhibitor dose.

As shown in FIG. 7, the concentration of enalaprilat increases as the concentration of enalapril decreases. This relationship is due to the conversion of enalapril to enalaprilat in vivo.

Although these data show a greater AUC for enalaprilat after administration of CVP3 than IVP5, AUC for IVP5 is consistent with the published AUC for enalaprilate after a dose of 0.5 mg / kg enalapril. The published PPK for enalaprilat after administration of enalapril in an amount of 0.5 mg / kg to dogs is 393 ng / h / ml (= 23.589 ng / min / ml) (see, for example, Toutain, PL, N. P. Lefebvre, and V Laroute. 2000. New insights on effect of kidney insufficiency on disposition of angiotensin converting enzyme inhibitors: case of enalapril and benazepril in dogs. J Pharmacol Exp Ther 292: 1094-103).

- FC Benazepril

As discussed above for enalapril, benazepril is a prodrug of active benazeprilat. Thus, the concentration of benazeprilat refers to the effective dose of ACE inhibitors for each formulation.

As shown in FIG. 10 and 11, the concentration of benazeprilat increases as benazepril is converted to benazeprilat.

Administration of IVPs of either 3 or 4 resulted in a greater BPC of active benazeprilat than CVP 2. The published BPC for benazeprilat after administration of benazepril in an amount of 0.5 mg / kg to dogs is 230 ng / h / ml (= 13.790 ng / min. / ml) = 114.9 ng / h / ml for a dose of 0.25 mg / kg (see, for example, Toutain, PL, N. P. Lefebvre, and V. Laroute. 2000. New insights on effect of kidney insufficiency on disposition of angiotensin converting enzyme inhibitors: case of enalapril and benazepril in dogs. J Pharmacol Exp Ther 292: 1094-103). Results for IVP of both 3 and 4 are consistent with this value.

IVP 3 contains only benazepril, and IVP 4 contains benazepril and pimobendan as active ingredients. BPC of benzazeprilat is greater for IVP3 than for IVP4. The concentration of benazepril after IVP 4 administration has a higher Stax and AUC in the first 3 hours than for IVP 3, which may have contributed to a lower BAC of benzazepril for IVP 4.

findings

These results show that a liquid composition containing pimobendan and propylene glycol effectively administers pimobendan to the animal after oral administration. In addition, these results show the unexpected effectiveness of propylene glycol, as Сmax and PPC IVP1 significantly exceed these indicators of a similar IVP2 with no propylene glycol. In addition, the results show that a liquid composition containing a combination of pimobendan and either enalapril or benazepril with propylene glycol provides bioavailable amounts of both active agents when administered orally. In addition, a liquid formulation containing benazepril and propylene glycol provides bioavailable benazeprilat in dogs after oral administration.

It should be understood that in the present description, a reference to a prior art document is not an acknowledgment that said document is part of well-known knowledge in the art in Australia or in any other country.

In the following claims and in the preceding description of the present invention, unless the context requires otherwise to express the wording or necessary implied clause, the term “contain” or its variations, such as “contains” or “comprising”, is used in the sense of inclusion, those. to indicate the presence of these features, but does not exclude the presence or addition of additional features in various embodiments of the present invention.

Claims (39)

1. Orally bioavailable non-aqueous liquid composition containing at least 7 wt.% Propylene glycol of the total weight of the composition and a cardiotonic agent selected from the group consisting of pimobendan and levosimendan and their pharmaceutically and veterinarily acceptable salts; or an angiotensin converting enzyme inhibitor selected from the group consisting of enalapril, benazepril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, trandolapril, ramipril, quinapril, perindopril, lisinopril and their pharmaceutically acceptable veterin; or a combination of a cardiotonic agent selected from the group consisting of pimobendan and levosimendan and their pharmaceutically and veterinarily acceptable salts, and an angiotensin converting enzyme inhibitor selected from the group consisting of enalapril, benazepril, cilazapril, delapril, imidapril, moexipril, moexipril, temepripril, moexipril, temriprilopril, moexipril, ramipril, quinapril, perindopril, lisinopril and their pharmaceutically and veterinarily acceptable salts. 2. The liquid composition according to claim 1, containing a cardiotonic agent selected from the group consisting of pimobendan and levosimendan, and at least 7 wt.% Propylene glycol of the total weight of the composition. 3. The liquid composition according to claim 1, containing an angiotensin converting enzyme inhibitor selected from the group consisting of enalapril, benazepril, cilazapril, delapril, imidapril, moexipril, spiapril, temocapril, trandolapril, ramipril, quinapril, perindoprilirin and perindopril liripril, acceptable salts, and at least 7 wt.% propylene glycol of the total weight of the composition. 4. The liquid composition according to claim 1, containing at least 7 wt.% Propylene glycol of the total weight of the composition and an effective amount of a combination of a cardiotonic agent selected from the group consisting of pimobendan and levosimendan and an angiotensin converting enzyme inhibitor selected from the group consisting of enalapril, benazepril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, trandolapril, ramipril, quinapril, perindopril, lisinopril and their pharmaceutically and veterinarily acceptable salts. 5. The composition according to p. 1, characterized in that the cardiotonic agent is pimobendan and its pharmaceutically or veterinarily acceptable salts or a combination thereof. 6. The composition according to p. 1, characterized in that the angiotensin converting enzyme inhibitor is selected from the group consisting of enalapril, benazepril and their pharmaceutically and veterinarily acceptable salts. 7. The composition according to any one of paragraphs. 1-6, optionally containing one or more additional active agents. 8. The composition according to p. 7, characterized in that said additional active agent is a diuretic. 9. The composition according to p. 8, wherein the diuretic is selected from the group consisting of furosemide, hydrochlorothiazide, chlortalidone, bumetanide, ethacrylic acid, torasemide, chlortiazide, spironolactone, triamterene, amiloride and their pharmaceutically or veterinarily acceptable salts or a combination thereof . 10. The composition according to p. 9, characterized in that the diuretic is a furosemide or its pharmaceutically or veterinarily acceptable salt. 11. The composition according to p. 1, characterized in that the cardiotonic agent is present in an amount of 0.1 to 50 wt.% Of the total weight of the composition. 12. The composition according to p. 7, characterized in that the specified additional active agent is present in an amount of from 0.1 to 50 wt.% Of the total weight of the composition. 13. The composition according to p. 1, characterized in that the angiotensin-converting enzyme inhibitor is present in an amount of 0.1 to 50 wt.% Of the total weight of the composition. 14. The composition according to any one of paragraphs. 1-6 and 8-13, characterized in that the composition further comprises one or more pharmaceutically or veterinarily acceptable excipients. 15. The composition according to p. 14, wherein the pharmaceutically or veterinarily acceptable excipient is selected from the group consisting of a surfactant, a viscosity modifier, flavor enhancer, preservative and solvent, or a combination thereof. 16. The composition according to p. 15, characterized in that the surfactant is selected from the group consisting of acetoglycerides, diethylene glycol esters, diethylene glycol ethers, ethylene glycol esters, glyceryl behenate, glycerol mono- and diesters, glyceryl monocapriloconol oleate, , glyceryl stearates, cetostearyl ethers of macrogol, esters of macrogol / glycerol, macrogol-6-glyceryl caprylocaprate, macrogol-20-glyceryl monostearate, macrogol-15-hydroxystearate, acrogollaurates, macrogol lauryl ethers, macrogol monomethyl ethers, macrogololeates, macrogol oleyl ethers, macrogol-40-sorbitolheptaoleate, macrogolstearates, macrogolglycerolcocoates, nonoxynols, octoxynols, olefin polyamide, hydroxy-oxylaminoate, hydroxymethylate, hydroxy-oxylaminoate, hydroxy-oxylaminoate, hydroxymethylate polysorbates such as polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, polyvinyl alcohol, propylene glycol caprylates, propylene glycol diacetate Laurate, propylene glycol, propylene glycol monopalmitostearata, quillaia, sorbitan esters, sucrose esters, tyloxapol and triglitserildiizostearata or combinations thereof. 17. The composition according to p. 15, wherein the viscosity modifier is selected from the group consisting of polyethylene glycol, polypropylene glycol, microcrystalline cellulose, polyvinylpyrrolidine and hydroxypropyl cellulose, or a combination thereof. 18. The composition according to p. 15 or 17, characterized in that the viscosity modifier is present in an amount of from 0.05 to 50 wt.% Of the total weight of the composition. 19. The composition according to p. 15, characterized in that the preservative is selected from the group consisting of benzoic acid, sodium benzoate, sodium propionate, sorbic acid, benzyl alcohol, bronopol, chlorobutol, phenoxyethanol, o-phenoxyethanol, chlorhexidine salts, hydroxybenzoate derivatives, salts of phenylmercury, thiomersal, chlorocresol, cresol, phenol, benzalkonium chloride, cetrimide, alpha-tocopherol, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene and sodium metabisulfite or a combination thereof . 20. The composition according to p. 15 or 19, characterized in that the preservative is present in an amount of from 0.001 to 10 wt.% Of the total weight of the composition. 21. The composition according to p. 15, wherein the flavor enhancer is selected from the group consisting of acesulfame potassium, alitam, aspartame, acesulfame, benzaldehyde, caramel, cyclamic acid, denatonium benzoate, dibutyl sebacinate, erythritol, ethyl acetate, ethyl cinnamate, ethyl maltol , maltol, sodium glutamate, neohesperidine dihydrochalcone, neotam, raspberries, red cherries, saccharin, saffron, stevioside, sucrose octaacetate, cocoa, tributylacetyl citrate, vanilla, vanillin, xylitol, dextrose, sucrose or glucose or Combinations 22. The composition according to p. 15 or 21, characterized in that the flavor enhancer is present in an amount of from 0.1 to 40 wt.% Of the total weight of the composition. 23. The composition according to p. 15, characterized in that the solvent is selected from the group consisting of glycerol, ethanol, propanol, butanol, amyl acetate, amylene hydrate, butylene glycol, formalin glycerol, hexylene glycol, polyethylene glycol, PEG300, glycofurol, pyrrolidone, propan diacetate oils, olive oils, castor oil and peanut butter, or a combination thereof. 24. The composition according to p. 15 or 23, characterized in that the solvent is present in an amount of from 1 to 99.94 wt.%. 25. The composition according to any one of paragraphs. 1-6, 8-13, 15-17, 19, 21, 23, characterized in that the composition is suitable for oral administration. 26. The composition according to any one of paragraphs. 1-6, 8-13, 15-17, 19, 21, 23, characterized in that the composition is suitable for parenteral administration. 27. The composition according to any one of paragraphs. 1-6, 8-13, 15-17, 19, 21, 23, which is a composition for use in veterinary medicine or a pharmaceutical composition for use in humans. 28. The composition according to p. 27, which is a composition for use in veterinary medicine. 29. The use of a liquid composition according to any one of paragraphs. 1-28 to obtain a medicine for the treatment of heart disease and / or hypertension, wherein said heart disease is: a) primary heart disease selected from the group consisting of congestive heart failure (CHF), acute CHF, chronic compensated endocardiosis (DCE), dilated cardiomyopathy (DCMP), asymptomatic (latent) CHF, asymptomatic DCMP and chronic heart valve disease or combinations thereof, or b) a secondary heart disease selected from the group consisting of cardiovascular dysfunction and impaired renal perfusion during anesthesia, shock, expansion of the stomach, inversion of the intestines, myocardial ischemia and renal ischemia, or a combination thereof. 30. The application of claim 29, wherein the subject is a companion animal. 31. The application of claim 30, wherein the subject is a dog or cat. 32. The use according to any one of paragraphs. 29-31, characterized in that the indicated application is oral. 33. The use according to any one of paragraphs. 29-31, characterized in that the indicated application is parenteral. 34. A method of obtaining a composition according to any one of paragraphs. 1-28, comprising mixing at least 7 wt.% Propylene glycol of the total weight of the composition with a cardiotonic agent selected from the group consisting of pimobendan and levosimendan and their pharmaceutically and veterinarily acceptable salts; or an angiotensin converting enzyme inhibitor selected from the group consisting of enalapril, benzazepril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, trandolapril, ramipril, quinapril, perindopril, lisinopril and pharmaceutically acceptable; or a combination of a cardiotonic agent selected from the group consisting of pimobendan and levosimendan and their pharmaceutically and veterinarily acceptable salts, and an angiotensin converting enzyme inhibitor selected from the group consisting of enalapril, benazepril, cilazapril, delapril, imidapril, moexapril, temriprilipril, moepripril, , ramipril, quinapril, perindopril, lisinopril and their pharmaceutically and veterinarily acceptable salts.

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